3,(2,4,5-Trisubstituted benzoyl)-propionic acid and the salts thereof

ABSTRACT

A compound of the formula ##STR1## wherein R 1  is a C 1-4  alkoxy, R 2  is C 1-4  alkyl and R 3  is C 1-4  alkylthio or pharmaceutically acceptable salts thereof. The compounds of the present invention exhibit excellent choleretic activity.

This is a division of application Ser. No. 288,378, filed Sep. 12, 1973,now U.S. Pat. No. 3,973,169.

This invention relates to a novel 3-(trisubstituted benzoyl)-propionicacid and the production thereof.

Heretofore, there has been no report that benzoyl propionic acidderivatives have spasmolytic or relaxing action on a gall bladder, thecommon biliary duct, especially Oddi's sphincter.

The present inventors have found that a compound represented by thefollowing formula (I) has a strong spasmolytic or relaxing action on agall bladder, the common biliary duct, especially Oddi's sphincter aswell as strong choleretic activity and low toxicity: ##STR2## wherein R₁is an alkyl group of 1 to 4 carbons, an alkoxy group of 1 to 4 carbonsor hydroxyl, and R₂ and R₃ are, the same as or different from eachother, an alkyl group of 1 to 4 carbons, an alkoxy group of 1 to 4carbons, hydroxyl, halogen or an alkylthio group of 1 to 4 carbons orthey are, connecting with each other, an alkylenedioxy group of 1 to 3carbons, with the proviso that when R₁ is the alkoxy group, at least oneof R₂ and R₃ is the alkoxy group or the alkylthio group or R₂ and R₃are, connecting with each other, the alkylenedioxy, when R₁ is the alkylgroup or hydroxyl, R₂ and R₃ are, the same or different, the alkoxygroup, the alkylthio group or, connecting with each other, thealkylenedioxy, when R₂ and R₃ are methoxy, R₁ is an alkyl group of 2 or3 carbons, an alkoxy group of 2 to 4 carbons or hydroxyl and when R₂ ismethyl and R₃ is methoxy, R₁ is an alkoxy group of 2 to 4 carbons.

Referring to the formula (I), the alkyl group of R₁, R₂ or R₃ may beexemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyland tert. butyl. The alkoxy group of R₁, R₂ or R₃ may be exemplified bymethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec.butoxy and tert.butoxy. The halogen atom of R₂ or R₃ may be exemplified by chlorine,bromine, iodine and fluorine. The alkylthio group of R₂ or R₃ may beexemplified by methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio, sec. butylthio and tert. butylthio and the alkylenedioxygroup formed by connection of R₂ and R₃ may be exemplified bymethylenedioxy, ethylenedioxy, propylenedioxy.

The compound of the formula (I) can be produced by, for example,

1. reacting a compound of the formula (II) ##STR3## wherein R₁, R₂ andR₃ have the same meaning as defined above with a reactive derivative ofsuccinic acid such as succinic anhydride, succinic acid half ester halfhalide, succinic acid half ester half nitrile or succinic acid halfester and hydrolysing the resultant compound, if necessary.

2. subjecting a coupound of the formula (III) ##STR4## wherein R₁, R₂and R₃ have the same meaning as defined above to hydrogenation, and

3. treating a compound of the formula (IV) ##STR5## wherein R₁, R₂ andR₃ have the same meaning as defined above and R₅ and R₆ are the same ordifferent from each other, esterified carboxyl group or cyano or one ofR₅ and R₆ is hydrogen and the other is cyano with an acid or an alkali.

4. and the compound (I) wherein R₁ is hydroxyl, namely the compound ofthe formula ##STR6## wherein R₈ and R₉ are, the same or different fromeach other, an alkoxy group of 1 to 4 carbons or an alkylthio group of 1to 4 carbons, or connecting with each other an alkylene-dioxy group of 1to 3 carbons can be produced by, for example, subjecting a compound ofthe formula Vi ##STR7## wherein R₇ is an alkoxy group and R₈ and R₉ havethe same meaning as above to ether cleavage reaction.

The esterified carboxyl group of R₅ and R₆ may be exemplified byalkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, etc.),aralkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.)and aryloxycarbonyl (phenoxycarbonyl, tolyloxycarbonyl, etc.).

An alkoxy group of R₇, R₈ and R₉, an alkylthio group and analkylenedioxy group of R₈ and R₉ may be the same as those of R₁, R₂ andR₃.

The manner for the production of the compound (I) by the reactionbetween the compound (II) and the reactive derivative of succinic acidvaries with the kind of reactive derivatives of succinic acid. Typicalproduction methods are as follows:

1-A. The reaction between the compound (II) and succinic anhydride givesdirectly the compound (I).

1-B. The reaction between the compound (II) and succinic acid half esterhalf halide such as β-methoxycarbopropionyl chloride andβ-ethoxycarbopropionyl chloride or succinic acid half ester half nitrilesuch as methyl β-cyanopropionate and ethyl β-cyanopropionate gives theester corresponding to the compound (I) and the hydrolysis of the estergives the compound (I).

1-C. The reaction between the compound (II) and a succinic acid halfester such as monomethyl succinate and monoethyl succinate in thepresence of polyphosphoric acid or polyphosphoric acid ester gives theester corresponding to the compound [I], and the hydrolysis of the estergives the compound [I].

The reaction of the above (1-A) or (1-B) is advantageously carried outin a suitable inert solvent such as an aromatic hydrocarbon or itsderivative (e.g. benzene, toluene, xylene, nitrobenzene), halogenoaliphatic hydrocarbon (e.g. methylene chloride, chloroform, carbontetrachloride, ethylene dichloride, ethylene tetrachloride), ether (e.g.ethyl ether, propyl ether, isopropyl ether, ethyleneglycoldimethylether, ethyleneglycol diethylether) and carbon disulfide, or amixture of two or more of them. It is desirable to carry out thereaction under anhydrous conditions and in the presence of a metalchloride such as anhydrous aluminum chloride, stannic chloride, zincchloride and titanium tetrachloride or a mixture of two or more of them.The reaction temperature is, generally, -70° to 200° C. and preferably-10° to 100° C. The introduction of dry hydrogen chloride to thereaction system can serve to accelerate the desired reaction.

The reaction of the above (1-C) may conveniently be carried out in theabsence of a solvent. In this reaction, any polyphosphoric acid orpolyphosphoric acid ester can be employed. Generally, it may be used inan amount of 2 to 20 times, preferably 5 to 10 times as much as thecompound (II). The reaction temperature is, in general, 0° to 250° C.,preferably 30° to 100° C. The other conditions may be the same as thoseof the reaction (1-A) or (1-B).

The reactions of (1-B) and (1-C) give the ester corresponding to thecompound (I). The ester, in the reaction mixture or isolated from thereaction mixture, is subjected to hydrolysis. The hydrolysis is carriedout under acidic or alkaline conditions. In case of alkaline conditions,the hydrolysis may conveniently be carried out in the presence of wateror a mixture of water and a lower alcohol such as methanol and ethanolin the presence of an alkaline substance such as sodium hydroxide orpotassium hydroxide, sodium bicarbonate, sodium carbonate, potassiumcarbonate at a temperature ranging from about -10° to 150° C. In case ofacidic conditions, the hydrolysis may conveniently be carried out inwater or a mixture of water and a lower alcohol such as methanol andethanol, an ether such as tetrahydrofuran and dioxane or an organic acidsuch as formic acid and acetic acid in the presence of a mineral acidsuch as hydrochloric acid, sulfuric acid and phosphoric acid at atemperature ranging from about -10° to 150° C. In the reaction of (1-C).after the condensation reaction between the compound (II) and thesuccinic acid half ester is completed, polyphosphoric acid orpolyphosphoric acid half ester is completed, polyphosphoric acid orpolyphosphoric acid ester in the reaction mixture is hydrolized by theaddition of water. The hydrolysis of the ester of the compound (I) iseasily carried out by the addition of an aqueous organic solvent andheating the reaction mixture.

Hydrogenation of the reaction (2) mentioned above may be carried out ina conventional manner such as catalytic reduction, a reduction using anacid with a metal such as zinc, iron or tin, or an amalgam such assodium amalgam. Catalytic reduction is generally carried out in asuitable solvent such as a lower alcohol (e.g. methanol, ethanol), anether (e.g. dioxane, tetrahydrofuran, isopropylether), acetic acid,ethyl acetate or water, or a mixture of one or more of them in thepresence of a catalyst such as palladium, platinum, rhodium, and nickel.

The compound (III) is a novel compound and it may be produced byreacting the compound (II) with a reactive derivative of maleic acid,i.e., maleic anhydride in a manner similar to that of (1-A), (1-B) or(1-C).

Treatment of the compound (IV) with an acid or an alkali can be carriedout in conditions similar to those of hydrolysis of the ester in thereaction (1-B) or (1-C).

Ether cleavage of the compound (VI) is carried out in the presence of aninorganic acid e.g. hydroiodic acid, hydrobromic acid, hydrochloricacid, a mixture of potassium iodide and polyphosphoric acid, an organicacid such as formic acid, acetic acid, trifluoroacetic acid or a mixtureof the organic acid and sodium iodide or potassium iodide. In additionto the acid, a suitable solvent such as water, a lower alcohol, aphenol, an organic acid or an ether such as dioxane and tetrahydrofuranmay be employed. The reaction temperature ranges, in general, from 0° C.to 200° C., preferably from 70° to 160° C.

In order to isolate the desired compound (I) from among any of thereaction mixtures described above, any conventional manner may beemployed. For example, steam distillation, extraction with a solvent oran alkaline solution, distillation or chromatography may beadvantageously employed.

The compound (I) may be obtained in the form of a pharmaceuticallyacceptable salt, such as metal salt with e.g. sodium, calcium,magnesium, lithium, ammonium salt ar amine salt.

The compound (I) thus produced is novel and has a strong spasmolytic orrelaxing action on the smooth muscles of a gall bladder, the commonbiliary duct, especially Oddi's sphincter as well as strong cholereticactivity and low toxicity. Therefore it is very useful as a therapeuticagent for cholerystopathy, especially biliary dyskinesia andcholelithiasis, or cholagogus.

The compound (I) can be administered orally in the form of a tablet,granules, powder, or by way of injection.

The typical effective daily dose of the compound (I) is usually about 20to 1000 mg, preferably, 50 to 300mg. when administered intravenously toan adult human. Of course, an increased or reduced dose may also beeffective depending upon the symptoms.

In the following examples, the relationship between parts by weight andparts by volume corresponds to the relationship between gram andmilliliter.

EXAMPLE 1

To a mixture of 7.5 parts by weight of 1,2,4,-triethoxybenzene, 40 partsby volume of tetrachloroethane and 7.5 parts by weight of succinicanhydride is added 23 parts by weight of anhydrous aluminum chloride andthe mixture is stirred for 1 hour at 25° C. and for another 2 hours at60° C. After addition of 50 parts by weight of ice and 50 parts byvolume of concentrated hydrochloric acid, the reaction mixture issubjected to steam distillation. After cooling, crystals separated fromthe remaining liquid are collected by filtration and recrystallized fromaqueous ethanol, whereby 2.5 parts by weight of3-(2',4',5'-triethoxybenzoyl)-propionic acid is obtained as colorlessneedles. m.p. 150°-151° C.

EXAMPLES 2 to 4

According to a manner similar to that of Example 1, the followingcompounds are obtained.

    ______________________________________                                        Example No.                                                                               Compound           mp. (° C.)                              ______________________________________                                        2        3-(2'-ethoxy-4',5'-dimethoxy-                                                                       156-158                                                 benzoyl)-propionic acid                                              3        3-(2'-n-butoxy-4',5'-dimethoxy-                                                                     156-157                                                 benzoyl)-propionic acid                                              4        3-(2',4',5'-tri-n-butoxybenzoyl)-                                                                   117-118                                                 propionic acid                                                       ______________________________________                                    

EXAMPLE 5

To the mixture of 9.0 parts by weight of 3,4-diethoxytoluene, 6.0 partsby weigth of succinic anhydride and 100 parts by volume of carbontetrachloride is added 27 parts by weight of anhydrous aluminumchloride. The mixture is stirred for 1 hour at 25° C. and mildlyrefluxed for 2 hours. After cooling, 70 parts by weight of ice and 70parts by volume of concentrated hydrochloric acid are added to themixture. Methylenedichloride is further added to the mixture and thewhole mixture is shaken. The organic solvent layer is separated andextracted with a 2N-aqueous solution of sodium carbonate. The aqueoussolution is adjusted with diluted hydrochloric acid to pH 2.5, whereby3-(2'-methyl-4',5'-diethoxybenzoyl)-propionic acid is obtained ascrystals. Recrystallization of the crystals gives 10.0 parts by weightof colorless plates melting at 116°-117° C.

EXAMPLES 6-14

According to a similar manner to that of Example 5, the followingcompounds are produced.

    ______________________________________                                        Example                                                                       No.       Compound             mp. (° C.)                              ______________________________________                                         6     3-(2',4'-dimethoxy-5'-chlorobenzoyl)-                                                                 185-187                                               propionic acid                                                          7     3-(2'-n-propyl-4',5'-dimethoxybenzoyl)-                                                               95-96                                                 propionic acid                                                          8     3-(2'-n-propyl-4'-methoxy-5'-ethoxy-                                                                   93                                                   benzoyl)-propionic acid                                                 9     3-(2'-n-propyl-4'-methoxy-5'-n-propoxy-                                                                70                                                   benzoyl)-propionic acid                                                10     3-(2'-n-propyl-4'-methoxy-5'-n-butoxy-                                                                85-86                                                 benzoyl)-propionic acid                                                11     3-(2',4'-diethoxy-5'-chlorobenzoyl)-                                                                  172-173                                               propionic acid                                                         12     3-(2'-methoxy-4'-t.-butyl-5'-ethoxy-                                                                  135-137                                               benzoyl)-propionic acid                                                13     3-(2',4'-diethoxy-5'-ethylbenzoyl)-                                                                   153-155                                               propionic acid                                                         14     3-(2'-methoxy-4'-chloro-5'-methoxy-                                                                   186-188                                               benzoyl)-propionic acid                                                ______________________________________                                    

EXAMPLE 15

To the mixture of 13.6 parts by weight of 1-ethoxy-3,4-dimethoxybenzene,12 parts by weight of β-ethoxycarbopropionyl chloride and 65 parts byvolume of benzene is added 18 parts by weight of anhydrous stannicchloride over 25 minutes and the mixture is stirred at 25° C. for 1hour. The mixture is cooled at 5° C. and 130 parts by volume of 20%hydrochloric acid is added thereto on stirring. To the mixture is added250 parts by volume of methylene chloride and shaken. The methylenechloride layer is separated and extracted with a 5% aqueous solution ofsodium bicarbonate twice and then washed with water twice. After dryingwith anhydrous calcium chloride, the solvent is distilled off.

To the residue are added 120 parts by volume of methanol and 95 parts byvolume of 1N-methanolic potassium hydroxide. The mixture is stirred at60° C. for 1 hour. After removal of methanol by distillation underreduced pressure, to the residue are added 150 parts by volume of waterand 100 parts by volume of methylene chloride, and the mixture isshaken. The aqueous layer is separated and adjusted to pH 2.5 withconcentrated hydrochloric acid, whereby 14 parts by weight of3-(2'-ethoxy-4',5'-dimethoxybenzoyl)-propionic acid as pale yellowcrystals. mp.156°-158° C.

EXAMPLES 16-23

After a manner similar to that of Example 15, the following compoundsare obtained.

    ______________________________________                                        Example                                                                       No.       Compound             mp. (° C.                               ______________________________________                                        16     3-(2',4',5'-triethoxybenzoyl)-                                                                        150-151                                               propionic acid                                                         17     3-(2'-n-butoxy-4',5'-dimethoxy-                                                                       156-157                                               benzoyl)-propionic acid                                                18     3-(2'-methoxy-4',5'-methylenedioxy-                                                                   140-141                                               benzoyl)-propionic acid                                                19     3-(2'-n-propyl-4',5'-methylenedioxy-                                                                  138-139                                               benzoyl)-propionic acid                                                20     3-(2'-n-propyl-4'-methoxy-5'-n-butoxy-                                                                85-86                                                 benzoyl)-propionic acid                                                21     3-(2'-ethoxy-4'-methyl-5'-methylthio-                                                                 117-118                                               benzoyl)-propionic acid                                                22     3-(2'-methoxy-4'-chloro-5'-methoxy-                                                                   186-188                                               benzoyl)-propionic acid                                                23     3-(2'-methoxy-4'-t.-butylbenzoyl-5'-                                                                  135-137                                               ethoxy)-propionic acid                                                 ______________________________________                                    

EXAMPLE 24

In 30 parts by volume of dried ethylether are dissolved 3.0 parts byweight of 1,2,4-triethoxybenzene and 3.0 parts by weight of methylβ-cyanopropionate. To the solution are added 2.0 parts by weight ofanhydrous zinc chloride and 2.0 parts by weight of anhydrous aluminumchloride. Hydrogen chloride gas is passed through the mixture over 30minutes. The mixture is left standing at 15° C. for 15 hours and 100parts by volume of ethylether is added thereto. After removal of theupper layer, the residue is mixed with 100 parts by volume of 20%hydrochloric acid and refluxed for 30 minutes whereby pale yellowcrystals are separated. After cooling, the crystals are collected byfiltration (yield: 4.3 parts).

The crystals thus-obtained are mixed with 30 parts by volume of methanoland 50 parts by volume of 1N-methanolic potassium hydroxide and heatedfor 40 minutes. After removal of the solvent, the remaining liquid isdissolved in 70 parts by volume of water and neutralized withconcentrated hydrochloric acid, whereby 3.0 parts by weight of3-(2',4',5'-triethoxybenzoyl)-propionic acid is obtained as crystalsmelting at 150°-151° C.

EXAMPLE 25

According to a similar manner to that of Example 24,3-(2',4',5'-tri-n-butoxybenzoyl)-propionic acid is obtained as colorlesscrystals melting at 117°-118° C.

EXAMPLE 26

A mixture of 12 parts by weight of 3,4-diethoxytoluene, 10 parts byweight of succinic acid monoethyl ester and 100 parts by weight ofpolyphosphoric acid is heated at 50° C. for 1 hour. To the mixture isadded 200 parts by volume of icewater and the mixture is extracted withethylether. By distilling off the solvent 15 parts by weight of ethyl3-(2'-methyl-4',5'-diethoxybenzoyl)-propionate is obtained as crystalsmelting at 81°-82° C.

The crystals are added to a mixture of 70 parts by volume of methanoland 70 parts by volume of 1N-methanolic potassium hydroxide and heatedat 50° C. for 1 hour. After removal of methanol, the remaining liquid isdissolved in water and neutralized with concentrated hydrochloric acid,whereby 3-(2'-methyl-4',5'-diethoxybenzoyl)-propionic acid is obtainedas crystals. Recrystallization from aqueous methanol gives 12 parts byweight of colorless platelets melting at 116°-117° C.

EXAMPLES 27-32

According to a similar manner to that of Example 26, the followingcompounds are obtained.

    ______________________________________                                        Example No.                                                                               Compound           mp. (° C.)                              ______________________________________                                        27       3-(2'-methoxy-4'-t.-butyl-5'-                                                                       135-137                                                 ethoxybenzoyl)-propionic acid                                        28       3-(2'-n-propyl-4'-methoxy-5'-n-                                                                      70                                                     propoxybenzoyl)-propionic acid                                       29       3-(2',4',5'-tri-n-butoxybenzoyl)-                                                                   117-118                                                 propionic acid                                                       30       3-(2'-methoxy-4',5'-methylenedioxy-                                                                 140-141                                                 benzoyl)-propionic acid                                              31       3-(2'-n-butoxy-4',5'-dimethoxybenzoyl)-                                                             156-157                                                 propionic acid                                                       32       3-(2',5'-diethoxy-4'-methylbenzoyl)-                                                                128-129                                                 propionic acid                                                       ______________________________________                                    

EXAMPLE 33

To a 50% (weight/volume) chloroform solution of polyphosphoric acidester are added 5 parts by weight of 1,2,4-triethoxybenzene and 3 partsby weight of succinic acid half methyl ester. The mixture is heated at50° C. for 1 hour and mixed with 50 parts by volume of ice-water and 30parts by volume of chloroform and then stirred for 40 minutes at 26° C.

The chloroform layer is separated and washed with water and dried. Thesolvent is distilled off. To the residue is added 30 parts by volume ofmethanol and 30 parts by volume of 1N-methanolic potassium hydroxide.The mixture is stirred for 40 minutes at 50° C. and the solvent isdistilled off. The residue is dissolved in 100 parts by volume of waterand washed with 30 parts by volume of diethylether. The pH of themixture is adjusted to 2.5 with concentrated hydrochloric acid whereby3-(2',4',5'-triethoxybenzoyl)-propionic acid is obtained as crsytals.Recrystallization of the crystals from aqueous acetone gives 4.1 partsby weight of colorless plates melting at 150°-151° C.

EXAMPLE 34

To a mixture of 2.1 parts by weight of 1,2,4-triethoxybenzene, 1.2 partsby weight of maleic anhydride and 30 parts by volume of carbontetrachloride is added 5.2 parts by weight of anhydrous aluminumchloride. The mixture is stirred for 1 hour and heated at 50° C. foranother 1 hour. After cooling, concentrated hydrochloric acid and iceare added to the mixture. The mixture is extracted withmethylenechloride and the methylenechloride layer is washed with waterand dried over anhydrous sodium sulfate. Upon removing the solvent bydistillation, 3-(2',4',5'-triethoxybenzoyl)-trans-acrylic acid isobtained as crystals. Recrystallization from a mixture of ethanol andbenzene gives yellow needles melting at 192°-194° C.

A mixture of 1.0 part by weight of3-(2',4',5'-triethoxybenzoyl)-trans-acrylic acid, 50 parts by volume ofmethanol and 0.2 part by weight of 5% palladium-charcoal is subjected tocatalytic reduction at 25° C. under atmospheric pressure for 1 hour.After removal of the catalyst by filtration, the filtrate is evaporatedand the residue is recrystallized from aqueous ethanol to give 0.85 partby weight of 3-(2',4',5'-triethoxybenzoyl)-propionic acid as pale yellowneedles melting at 150°-151° C.

EXAMPLES 35-38

According to a similar manner to that of Example 34, the followingstarting 3-(trisubstituted benzoyl)-acrylic acids and the objective3-(trisubstituted benzoyl)-propionic acids are obtained.

    ______________________________________                                        Ex.  Starting Compound                                                                             Cata-   Objective compound                               No.  Compound   mp(° C.)                                                                        lyst  Compound mp(° C.)                       ______________________________________                                             3-(2'-methyl-             3-(2'-methyl-                                  35   4',5'-     126 -    Pd-C  4',5'-   116 -                                      diethoxy-  127.5          diethoxy-                                                                              117                                        benzoyl)-                 benzoyl)-                                           trans-acrylic             propionic                                           acid                      acid                                                3-(2',4'-                 3-(2',4'-                                      36   diethoxy-5'-                                                                             198      Na-   diethoxy-5'-                                                                           172 -                                      chloro-             ama-  chloro-  173                                        benzoyl)-           lgam  benzoyl)-                                           trans-acrylic             propionic                                           acid                      acid                                                3-(2'-n-                  3-(2'-n-                                       37   propyl-4'- 91 -     Pd-C  propyl-4'-                                                                             85 -                                       methoxy-5'-n-                                                                            93             methoxy-5'-n-                                                                          86                                         butoxy-                   butoxy-                                             benzoyl)-                 benzoyl)-                                           trans-acrylic             propionic                                           acid                      acid                                                3-(2'-n-                  3-(2'-n-                                       38   propyl-4'- 103 -    Pd-C  propyl-4'-                                                                             85 -                                       methoxy-5'-n-                                                                            106            methoxy-5'-n-                                                                          86                                         butoxy-                   butoxy-                                             benzoyl)-cis-             benzoyl)-                                           acrylic acid              propionic acid                                 ______________________________________                                    

EXAMPLE 39

To a mixture of 0.56 part by weight of diethyl malonate, 0.2 part byweight of 50% sodium hydride and 8.0 parts by volume of driedtetrahydrofuran is added 1.0 part by weight of2',4',5'-triethoxyphenacyl chloride little by little at 25° C., and isstirred for 10 hours. To the mixture are added 8 parts by volume ofethyl acetate and 50 parts by weight of ice water and shaken. The ethylacetate layer is separated and washed with water and then dried andevaporated. The residue is recrystallized from methanol to give ethyl3-(2', 4',5'-triethoxybenzoyl)-2-ethoxycarbopropionate as pale yellowplates melting at 97°-98° C.

A mixture of 1.5 part by weight of ethyl3-(2',4',5'-triethoxybenzoyl)-2-ethoxycarbopropionate, 30 parts byvolume of dioxane and 30 parts by volume of 30% sulfuric acid is heatedat 120° C. for 2 hours. The mixture is diluted with water and extractedwith chloroform. The chloroform layer is separated and washed with waterand dried. The solvent is distilled off, whereby 1.1 part by weight of3-(2',4',5'-triethoxybenzoyl)-propionic acid is obtained.Recrystallization from aqueous methanol gives pale yellow needlesmelting at 150°-151° C.

EXAMPLE 40

According to a similar manner to that of Example 39, 2.0 parts by weightof 2',4',5'-triethoxyphenacylchloride is reacted with 0.9 part by weightof ethyl cyanacetate and 0.34 part by weight of 50% sodium hydride. Thereaction mixture is subjected to chromatography with silica gel andeluted with benzene whereby 0.62 part by weight of3-(2',4'-5'-triethoxybenzoyl)-2-ethoxycarbopropionitrile is obtained ascrystalls. Recrystallization from methanol gives colorless platesmelting at 109°-110° C.

One part by weight of3-(2',4',5'-triethoxybenzoyl)-2-ethoxycarbopropionitrile is treated with14 parts by volume of 4N-hydrochloric acid and 40 parts by volume ofacetic acid at 100°-110° C. for 2 hours. The reaction mixture is treatedaccording to the same manner as that of Example 39 whereby 0.65 part byweight of 3-(2',4',5'-triethoxybenzoyl)-propionic acid is obtained.mp.150°-151° C.

EXAMPLE 41

To a mixture of 5.0 parts by weight of3-methoxy-4-n-butoxy-n-propylbenzene, 4.0 parts by weight ofβ-chloropropionyl chloride and 20 parts by volume of dried benzene isadded dropwise 9.0 parts by weight of stannic chloride dissolved in 5parts by volume of carbon tetrachloride on cooling below 20° C. Afterstirring for 2 hours, about 200 parts by volume of ice-water is added tothe mixture and thereto is added 200 parts by volume of benzene and thenthe mixture is shaken. The benzene layer is separated and washed withwater and dried. The solvent is distilled off and the residue iscrystallized from petroleum ether wherebyΩ-chloro-(2'-n-propyl-4'-methoxy-5'-n-butoxy)-propiophenone is obtainedas colorless prisms. m.p. 42°-43° C.

To 30 parts by volume of dimethylsulfoxide is added 6.0 parts by weightof Ω-chloro-(2'-n-propyl-4'-methoxy-5'-n-butoxy)-propiophenone. To themixture added 1.0 part by weight of sodium cyanide. The mixture isstirred for 2 hours at 80° C. The reaction mixture is mixed withice-water and extracted with benzene. The benzene layer is washed withwater and dried. The solvent is distilled off and the residue iscrystallized from aqueous ethanol to give3-(2'-n-propyl-4'-methoxy-5'-n-butoxybenzoyl)-propionitrile is obtainedas colorless needles melting at 76° C.

A mixture of 1 part by weight of3-(2'-n-propyl-4'-methoxy-5'-n-butoxybenzoyl)-propionitrile, 2 parts byvolume of concentrated hydrochloric acid, 5 parts by volume of water and5 parts by volume of acetic acid is stirred for 1.5 hour at 80°-90° C.The reaction mixture is diluted with water and extracted withmethylenechloride and the extract is washed, dried and concentrated. Theresidue is mixed with n-hexane and cooled whereby 0.8 part by weight of3-(2'-n-propyl-4'-methoxy-5'-n-butoxybenzoyl)-propionic acid is obtainedas crystals. Recrystallization from a mixture of methylenechloride andn-hexane gives pale yellow crystals melting at 85°-86° C.

EXAMPLE 42

A mixture of 2 parts by weight of3-(2',4',5'-triethoxybenzoyl)-propionic acid, 12 parts by weight ofpotassium iodide and 60 parts by volume of formic acid is refluxed for 3hours and the solvent is distilled off. The residue is mixed with 50parts by volume of water and stirred for a while and then insolublesubstance is collected by filtration. The substance is washed with waterand recrystallized from aqueous ethanol whereby 1.2 part by weight of3-(2'-hydroxy-4',5'-diethoxybenzoyl)-propionic acid is obtained ascolorless crystals melting at 142°-144° C.

EXAMPLES 43-45

According to a similar manner to that of Example 42, the followingcompounds are obtained.

    ______________________________________                                        Example No.                                                                               Compound           mp. (° C.                               ______________________________________                                        43       3-(2'-hydroxy-4',5'-dimethoxybenzoyl)-                                                              162-163                                                 propionic acid                                                       44       3-(2'-hydroxy-4',5'-methylenedioxy-                                                                 180-182                                                 benzoyl)-propionic acid                                              45       3-(2'-hydroxy-4',5'-n-butoxybenzoyl)-                                                               127                                                     propionic acid                                                       ______________________________________                                    

EXAMPLE 46

In 50 parts by volume of ethyl acetate are dissolved 9 parts by weightof 2-methyl-4,5-diethoxyacetophenone and 12 parts by weight of cupricbromide and the mixture is refluxed for 30 minutes. After removal ofwhite inorganic substance by filtration, the filtrate is washed withwater and dried over anhydrous sodium sulfate and the solvent isdistilled off. The residue is recrystallized from petroleum ether togive 8.6 parts by weight of 2'-methyl-4',5'-diethoxyphenacylbromide ascolorless crystals.

To a mixture of 15 parts by volume of dry tetrahydrofuran, 0.6 part byweight of diethyl malonate and 0.22 part by weight of sodium hydride isadded 0.7 part by weight of 2'-methyl-4',5═-diethoxyphenacylbromide andthe mixture is stirred for 12 hours. The reaction mixture is poured intowater and acidified with diluted hydrochloric acid and extracted withethyl acetate. The extract is washed with water, dried over anhydroussodium sulfate, and the solvent is distilled off, whereby 0.68 part byweight of ethyl3-(2'-methyl-4',5'-diethoxybenzoyl-2-ethoxycarbopropionate is obtainedas oily substance. The substance shows the following IR absorption andNMR spectrum.

IR absorption: δ_(max) ^(film) cm⁻ ¹ 1750-1715 (ester), 1665 (ketone)

NMR spectrum (60MC, in CDC1₃, δ, p.p.m.):

1.1-1.6 (12H, triplet, --CH₂ --CH₃), 2.42 (3H, singlet, aromatic CH₃),3.35 (2H, doublet, --COCH.sub. 2 --), 3.6-4.4 (9H, quartet andmultiplet, --CH₂ --CH₃ and --CH(COOC₂ H₅)₂), 6.62 (1H, singlet, C'₃--H), 7.28 (1H, singlet, C'₆ --H)

According to a similar manner to that of Example 39,3-(2'-methyl-4',5'-diethoxybenzoyl)-propionic acid is obtained fromethyl 3-(2'-methyl-4',5'-diethoxybenzoyl-2-ethoxycarbopropionate.

EXAMPLES 47-49

According to a similar manner to that of Example 41, the followingstarting 3-(trisubstituted benzoyl)-propionitriles and the objective3-(trisubstituted benzoyl)-propionic acids are obtained.

    __________________________________________________________________________    Example                                                                            Starting Compound   Objective compound                                   No.  Compound      mp (° C.)                                                                    Compound      mp (° C.)                       __________________________________________________________________________    47   3-(2',4',5'-triethoxy-                                                                      117-  3-(2',4',5'-triethoxy-                                                                      150-                                        benzoyl)-propionitrile                                                                       118  benzoyl)-propionic acid                                                                      151                                   48   3-(2',4'-diethoxy-5'-                                                                       141-  3-(2',4'-diethoxy-5'-                                                                       172-                                        chlorobenzoyl)-propio-                                                                       142  chlorobenzoyl)-propio-                                                                       173                                        nitrile             nic acid                                             49   3-(2'-ethoxy-4'-methyl-                                                                      99-  3-(2'-ethoxy-4'-methyl-                                                                     117-                                        5'-methylthiobenzoyl)-                                                                       100  5'-methylthiobenzoyl-propio-                                                                 118                                        propionitrile       nic acid                                             __________________________________________________________________________

What is claimed is:
 1. A compound of the formula ##STR8## wherein R₁ isan alkoxy group of 1 to 4 carbons, R₂ is an alkyl group of 1 to 4carbons and R₃ is an alkylthio group of 1 to 4 carbons orpharmaceutically acceptable salts thereof.
 2. A compound claimed inclaim 1 which is 3-(2'-ethoxy-4'-methyl-5'-methylthiobenzoyl) propionicacid.